tbuckley/cabot-search huggingface dataset:
Systematic investigation of allelic regulatory activity of schizophrenia-associated common variants
Authors: Jessica C. McAfee, Sool Lee, Jiseok Lee, Jessica L. Bell, Oleh Krupa, Jessica Davis, Kimberly Insigne, Marielle L. Bond, Nanxiang Zhao, Alan P. Boyle, Douglas H. Phanstiel, Michael I. Love, Jason L. Stein, W. Brad Ruzicka, Jose Davila-Velderrain, Sriram Kosuri, Hyejung Won
Journal: Cell Genomics (2023)

Genome-wide association studies (GWASs) have successfully identified 145 genomic regions that contribute to schizophrenia risk, but linkage disequilibrium makes it challenging to discern causal variants. We performed a massively parallel reporter assay (MPRA) on 5,173 fine-mapped schizophrenia GWAS variants in primary human neural progenitors and identified 439 variants with allelic regulatory effects (MPRA-positive variants). Transcription factor binding had modest predictive power, while fine-map posterior probability, enhancer overlap, and evolutionary conservation failed to predict MPRA-positive variants. Furthermore, 64% of MPRA-positive variants did not exhibit expressive quantitative trait loci signature, suggesting that MPRA could identify yet unexplored variants with regulatory potentials. To predict the combinatorial effect of MPRA-positive variants on gene regulation, we propose an accessibility-by-contact model that combines MPRA-measured allelic activity with neuronal chromatin architecture.
Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction
Authors: George J. Xu, Matthew A. Loberg, Jean-Nicolas Gallant, Quanhu Sheng, Sheau-Chiann Chen, Brian D. Lehmann, Sophia M. Shaddy, Megan L. Tigue, Courtney J. Phifer, Li Wang, Mario W. Saab-Chalhoub, Lauren M. Dehan, Qiang Wei, Rui Chen, Bingshan Li, Christine Y. Kim, Donna C. Ferguson, James L. Netterville, Sarah L. Rohde, Carmen C. Solórzano, Lindsay A. Bischoff, Naira Baregamian, Aaron C. Shaver, Mitra Mehrad, Kim A. Ely, Daniel W. Byrne, Thomas P. Stricker, Barbara A. Murphy, Jennifer H. Choe, Luciane T. Kagohara, Elizabeth M. Jaffee, Eric C. Huang, Fei Ye, Ethan Lee, Vivian L. Weiss
Journal: Cell Genomics (2023)

Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.
Polygenic prediction across populations is influenced by ancestry, genetic architecture, and methodology
Authors: Ying Wang, Masahiro Kanai, Taotao Tan, Mireille Kamariza, Kristin Tsuo, Kai Yuan, Wei Zhou, Yukinori Okada, Hailiang Huang, Patrick Turley, Elizabeth G. Atkinson, Alicia R. Martin
Journal: Cell Genomics (2023)

Polygenic risk scores (PRSs) developed from multi-ancestry genome-wide association studies (GWASs), PRSmulti, hold promise for improving PRS accuracy and generalizability across populations. To establish best practices for leveraging the increasing diversity of genomic studies, we investigated how various factors affect the performance of PRSmulti compared with PRSs constructed from single-ancestry GWASs (PRSsingle). Through extensive simulations and empirical analyses, we showed that PRSmulti overall outperformed PRSsingle in understudied populations, except when the understudied population represented a small proportion of the multi-ancestry GWAS. Furthermore, integrating PRSs based on local ancestry-informed GWASs and large-scale, European-based PRSs improved predictive performance in understudied African populations, especially for less polygenic traits with large-effect ancestry-enriched variants. Our work highlights the importance of diversifying genomic studies to achieve equitable PRS performance across ancestral populations and provides guidance for developing PRSs from multiple studies.
Gene-Level Analysis of Anthracycline-Induced Cardiomyopathy in Cancer Survivors
Authors: Noha Sharafeldin, Liting Zhou, Purnima Singh, David K. Crossman, Xuexia Wang, Lindsey Hageman, Wendy Landier, Javier G. Blanco, Paul W. Burridge, Yadav Sapkota, Yutaka Yasui, Gregory T. Armstrong, Leslie L. Robison, Melissa M. Hudson, Kevin Oeffinger, Eric J. Chow, Saro H. Armenian, Daniel J. Weisdorf, Smita Bhatia
Journal: JACC CardioOncology (2023)

Anthracyclines are highly effective in treating cancer, albeit with increased cardiomyopathy risk. Although risk is attributed to associations with single nucleotide polymorphisms (SNPs), multiple SNPs on a gene and their interactions remain unexamined. This study examined gene-level associations with cardiomyopathy among cancer survivors using whole-exome sequencing data. For discovery, 278 childhood cancer survivors (129 cases; 149 matched control subjects) from the COG (Children's Oncology Group) study ALTE03N1 were included. Logic regression (machine learning) was used to identify gene-level SNP combinations for 7,212 genes and ordinal logistic regression to estimate gene-level associations with cardiomyopathy. Models were adjusted for primary cancer, age at cancer diagnosis, sex, race/ethnicity, cumulative anthracycline dose, chest radiation, cardiovascular risk factors, and 3 principal components. Statistical significance threshold of 6.93 × 10−6 accounted for multiple testing. Three independent cancer survivor populations (COG study, BMTSS [Blood or Marrow Transplant Survivor Study] and CCSS [Childhood Cancer Survivor Study]) were used to replicate gene-level associations and examine SNP-level associations from discovery genes using ordinal logistic, conditional logistic, and Cox regression models, respectively. Median age at cancer diagnosis for discovery cases and control subjects was 6 years and 8 years, respectively. Gene-level association for P2RX7 (OR: 0.10; 95% CI: 0.04-0.27; P = 2.19 × 10−6) was successfully replicated (HR: 0.65; 95% CI: 0.47-0.90; P = 0.009) in the CCSS cohort. Additional signals were identified on TNIK, LRRK2, MEFV, NOBOX, and FBN3. Individual SNPs across all discovery genes, except FBN3, were replicated. In our study, SNP sets having 1 or no copies of P2RX7 variant alleles were associated with reduced risk of cardiomyopathy, presenting a potential therapeutic target to mitigate cardiac outcomes in cancer survivors.
Affirmation-support, parental conflict, and mental health outcomes of transgender and gender diverse youth
Authors: Natasha Belmont, Timothy J. Cronin, Christopher A. Pepping
Journal: International Journal of Transgender Health (2023)

Background: Transgender and gender diverse young people (TGDY) are at higher risk of psychosocial distress relative to their cisgender counterparts. TGDY rely heavily on their parents to support their desired affirmation and to facilitate access to legal and medical affirmation. While it is well understood that parent conflict negatively impacts the well-being of children and young people, little is known about how parental conflict and parental affirmation support are related to TGDY well-being.
Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus
Authors: Jiamei Le, Yilong Chen, Wei Yang, Ligong Chen, Jianping Ye
Journal: Acta Pharmaceutica Sinica B (2023)

Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (
ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells
Authors: Mingjin Wang, Weida Wang, Shen You, Zhenyan Hou, Ming Ji, Nina Xue, Tingting Du, Xiaoguang Chen, Jing Jin
Journal: Acta Pharmaceutica Sinica B (2023)

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C–X–C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.
Maxillary sinus floor augmentation: a review of current evidence on anatomical factors and a decision tree
Authors: Mingyue Lyu, Dingyi Xu, Xiaohan Zhang, Quan Yuan
Journal: International Journal of Oral Science (2023)

Abstract Maxillary sinus floor augmentation using lateral window and crestal technique is considered as predictable methods to increase the residual bone height; however, this surgery is commonly complicated by Schneiderian membrane perforation, which is closely related to anatomical factors. This article aimed to assess anatomical factors on successful augmentation procedures. After review of the current evidence on sinus augmentation techniques, anatomical factors related to the stretching potential of Schneiderian membrane were assessed and a decision tree for the rational choice of surgical approaches was proposed. Schneiderian membrane perforation might occur when local tension exceeds its stretching potential, which is closely related to anatomical variations of the maxillary sinus. Choice of a surgical approach and clinical outcomes are influenced by the stretching potential of Schneiderian membrane. In addition to the residual bone height, clinicians should also consider the stretching potential affected by the membrane health condition, the contours of the maxillary sinus, and the presence of antral septa when evaluating the choice of surgical approaches and clinical outcomes.
Cystic Focal Ectasia Due to Moraxella Keratitis Identified in Formalin-Fixed Tissue
Authors: Evan J. Warner, Yasmin S. Bradfield, Julia Shatten
Journal: Ophthalmology (2023)

A 21-month-old with Moebius syndrome presented with parental concern of increased right eye rubbing. The eyes had symmetric moderate conjunctival injection, with 6-8 mm lagophthalmos bilaterally. Examination under anesthesia revealed a soft eye with shallow anterior chamber, and a 5 × 4 mm, minimally opaque cystic protuberance in the right nasal cornea that was subtlety Seidel-positive (A, B). Intraoperative OCT demonstrated large cystic fluid cavities throughout the effected corneal stroma, with communication to the anterior chamber (C). A therapeutic penetrating keratoplasty was performed, and Gram stain of the corneal button revealed Gram-negative diplococci (D). 16s ribosomal RNA sequencing identified Moraxella nonliquifaciens within the formalin-fixed tissue. (Magnified version of Figure A-D is available online at www.aaojournal.org).
Use of DPP4 Inhibitors and GLP-1 Receptor Agonists and Risk of Intestinal Obstruction: Scandinavian Cohort Study
Authors: Peter Ueda, Viktor Wintzell, Mads Melbye, Björn Eliasson, Jonas Söderling, Soffia Gudbjörnsdottir, Kristian Hveem, Christian Jonasson, Henrik Svanström, Anders Hviid, Björn Pasternak
Journal: Clinical Gastroenterology and Hepatology (2023)

Concerns have been raised that the incretin-based diabetes drugs dipeptidyl peptidase 4 (DPP4) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists may increase the risk of intestinal obstruction. We aimed to assess the association between use of DPP4 inhibitors and GLP-1 receptor agonists and the risk of intestinal obstruction.
Endoscopic Resection of Cecal Neoplasia With Full-thickness Resection of the Appendiceal Stump Using Double-layered Suturing
Authors: Daiki Kitagawa, Shunsuke Yoshii, Ryu Ishihara
Journal: Clinical Gastroenterology and Hepatology (2023)

A 73-year-old woman with a history of appendectomy for acute appendicitis was diagnosed with a 20-mm laterally spreading tumor involving the appendiceal orifice site (Figure A). Although computed tomography scan revealed the whole image of the appendiceal stump, the tumor margin could not be confirmed endoscopically. Complete resection of the tumor using conventional endoscopic submucosal dissection procedure was difficult, and endoscopic excision, including full-thickness resection of the appendiceal stump, was performed. After a circumferential mucosal incision, a multiloop traction device (Boston Scientific Co) was applied, and the severely fibrotic submucosal layer was visualized. As submucosal dissection proceeded, a hollow appeared at the depression site of appendiceal stump (Figure B). Successful en bloc resection was achieved, and a defect in the muscle layer was confirmed (Figure C). The post-resection ulcer, including the muscular defect, was robustly closed using the double-layered suturing method (Figure D). The patient was discharged 5 days postoperatively without any adverse events. Histological examination revealed an 18-mm serrated lesion with negative resection margins. The development of traction devices and recent advancements in novel closure techniques can lead to further expansion of indications for endoscopic resection with the clinical benefit of avoiding invasive surgery. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0NDgxOTY5YzUxMjkyMmMwYjA0MmFlZmRmNDg2ZWJmZCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzE1MTAwNTY2fQ.N4LGwC9zQopypRl9LtQqex41va7cjmz6_aBhGCHT4WymKb7tiMbvOVo99NPtEOClY7IeE6BZlLZgcdzS1UFk7ieBCslpk1fxFEzPuTEmTkkC-C50Zo9LJc69-t7se1YQm5ST_XwEEY1aQJphJ_VrY1o3VkHac8nu_zTUoBlyUPWWvXTmL7qLlXgP1Hnq7RgiH4RiFru53pE1LcgF_DrGWLDyubR6Ug37wNBSA-kK-cR_XUbFC-kUE7vJcNSq08GyOPyoLEHfKDuhheqXde462h5FRlRoQpqJf9kk4zvn06zXbEs5RtyoHx-AEXYc5J75w62khx0gdVyIrQiVhshmkw Download .mp4 (50.59 MB) Help with .mp4 files Video
Prevalence and Predictors of Barrett’s Esophagus After Negative Initial Endoscopy: Analysis From Two National Databases
Authors: Lovekirat Dhaliwal, Amrit K. Kamboj, J. Lucas Williams, Apoorva K. Chandar, Karan Sachdeva, Erin Gibbons, Ramona Lansing, Melissa Passe, Jaime A. Perez, Katelin L.R. Avenir, Scott A. Martin, Cadman L. Leggett, Amitabh Chak, Gary W. Falk, Sachin Wani, Nicholas J. Shaheen, John B. Kisiel, Prasad G. Iyer
Journal: Clinical Gastroenterology and Hepatology (2023)
Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ)
Authors: Malin Fromme, Karim Hamesch, Carolin V. Schneider, Mattias Mandorfer, Monica Pons, Katrine H. Thorhauge, Vitor Pereira, Jan Sperl, Sona Frankova, Matthias C. Reichert, Federica Benini, Barbara Burbaum, Moritz Kleinjans, Samira Amzou, Laura Rademacher, Lisa Bewersdorf, Jef Verbeek, Frederik Nevens, Joan Genesca, Marc Miravitlles, Alexa Nuñez, Benedikt Schaefer, Heinz Zoller, Sabina Janciauskiene, Johan Waern, António Oliveira, Luís Maia, Carolina Simões, Ravi Mahadeva, Daniel D. Fraughen, Michael Trauner, Aleksander Krag, Frank Lammert, Robert Bals, Nadine T. Gaisa, Elmar Aigner, William J. Griffiths, Helmut Denk, Alexander Teumer, Noel G. McElvaney, Alice M. Turner, Christian Trautwein, Pavel Strnad
Journal: Clinical Gastroenterology and Hepatology (2023)
Withdrawal of Immunomodulators or TNF Antagonists in Patients With Inflammatory Bowel Diseases in Remission on Combination Therapy: A Systematic Review and Meta-analysis
Authors: David J. Katibian, Virginia Solitano, D. Brent Polk, Tran Nguyen, Christopher Ma, Gaurav Syal, Taku Kobayashi, Toshifumi Hibi, Sine Buhl, Mark Andrew Ainsworth, Vipul Jairath, Siddharth Singh
Journal: Clinical Gastroenterology and Hepatology (2023)
Accuracy, Reliability, and Comprehensibility of ChatGPT-Generated Medical Responses for Patients With Nonalcoholic Fatty Liver Disease
Authors: Nicola Pugliese, Vincent Wai-Sun Wong, Jörn M. Schattenberg, Manuel Romero-Gomez, Giada Sebastiani, Alessio Aghemo, Laurent Castera, Cesare Hassan, Pinelopi Manousou, Luca Miele, Raquel Peck, Salvatore Petta, Luca Valenti, Zobair M. Younossi
Journal: Clinical Gastroenterology and Hepatology (2023)

Nonalcoholic fatty liver disease (NAFLD) is an increasing global health problem and is expected to become the leading indication for liver transplantation.
Treatment of primary plasma cell leukaemia with carfilzomib and lenalidomide-based therapy (EMN12/HOVON-129): final analysis of a non-randomised, multicentre, phase 2 study
Authors: Niels W C J van de Donk, Monique C Minnema, Bronno van der Holt, Fredrik Schjesvold, Ka Lung Wu, Annemiek Broijl, Wilfried W H Roeloffzen, Alain Gadisseur, Giuseppe Pietrantuono, Ludek Pour, Vincent H J van der Velden, Thomas Lund, Massimo Offidani, Mariella Grasso, Luisa Giaccone, Wida Razawy, Paola Tacchetti, Katia Mancuso, Trine Silkjaer, Jo Caers, Sonja Zweegman, Roman Hájek, Reuben Benjamin, Annette Juul Vangsted, Mario Boccadoro, Francesca Gay, Pieter Sonneveld, Pellegrino Musto
Journal: The Lancet Oncology (2023)
Spatio-temporal physics-informed learning: A novel approach to CT perfusion analysis in acute ischemic stroke
Authors: Lucas de Vries, Rudolf L.M. van Herten, Jan W. Hoving, Ivana Išgum, Bart J. Emmer, Charles B.L.M. Majoie, Henk A. Marquering, Efstratios Gavves
Journal: Medical Image Analysis (2023)

CT perfusion imaging is important in the imaging workup of acute ischemic stroke for evaluating affected cerebral tissue. CT perfusion analysis software produces cerebral perfusion maps from commonly noisy spatio-temporal CT perfusion data. High levels of noise can influence the results of CT perfusion analysis, necessitating software tuning. This work proposes a novel approach for CT perfusion analysis that uses physics-informed learning, an optimization framework that is robust to noise. In particular, we propose SPPINN: Spatio-temporal Perfusion Physics-Informed Neural Network and research spatio-temporal physics-informed learning. SPPINN learns implicit neural representations of contrast attenuation in CT perfusion scans using the spatio-temporal coordinates of the data and employs these representations to estimate a continuous representation of the cerebral perfusion parameters. We validate the approach on simulated data to quantify perfusion parameter estimation performance. Furthermore, we apply the method to in-house patient data and the public Ischemic Stroke Lesion Segmentation 2018 benchmark data to assess the correspondence between the perfusion maps and reference standard infarct core segmentations. Our method achieves accurate perfusion parameter estimates even with high noise levels and differentiates healthy tissue from infarcted tissue. Moreover, SPPINN perfusion maps accurately correspond with reference standard infarct core segmentations. Hence, we show that using spatio-temporal physics-informed learning for cerebral perfusion estimation is accurate, even in noisy CT perfusion data. The code for this work is available at https://github.com/lucasdevries/SPPINN.
Bone mineral density estimation from a plain X-ray image by learning decomposition into projections of bone-segmented computed tomography
Authors: Yi Gu, Yoshito Otake, Keisuke Uemura, Mazen Soufi, Masaki Takao, Hugues Talbot, Seiji Okada, Nobuhiko Sugano, Yoshinobu Sato
Journal: Medical Image Analysis (2023)
Living on the edge: network neuroscience beyond nodes
Authors: Richard F. Betzel, Joshua Faskowitz, Olaf Sporns
Journal: Trends in Cognitive Sciences (2023)

Network neuroscience has emphasized the connectional properties of neural elements - cells, populations, and regions. This has come at the expense of the anatomical and functional connections that link these elements to one another. A new perspective - namely one that emphasizes 'edges' - may prove fruitful in addressing outstanding questions in network neuroscience. We highlight one recently proposed 'edge-centric' method and review its current applications, merits, and limitations. We also seek to establish conceptual and mathematical links between this method and previously proposed approaches in the network science and neuroimaging literature. We conclude by presenting several avenues for future work to extend and refine existing edge-centric analysis.
Fluorescence imaging deformability cytometry: integrating nuclear structure with mechanical phenotyping
Authors: Hector E. Muñoz, Jonathan Lin, Bonnie G. Yeh, Tridib Biswas, Dino Di Carlo
Journal: Med-X (2023)

Abstract Mechanical measurements of cells can provide unique insights into cell state and disease processes. The overall mechanical properties of cells can be heavily affected by the stiffest organelle, the nucleus. However, it is challenging to fully characterize internal nuclear structures in most cell mechanical measurement platforms. Here, we demonstrate single-cell deformability measurements of whole cells and stained nuclei in a fluorescence imaging flow cytometry platform. We also introduce bending energy derived metrics as a way to normalize measurements of cytoskeletal cortex and nuclear shape changes of cells and demonstrate the utility of relative deformability distributions to characterize populations of cells. We apply the platform to measure changes in cell biophysical properties during the process of NETosis, whereby neutrophils undergo drastic nuclear restructuring. We characterize cell size, deformability, and nuclear structure changes and their correlations in thousands of neutrophils undergoing NETosis, a process implicated in development of critical disease states, such as sepsis. This platform can aid in understanding heterogeneity in deformability in cell populations and how this may be influenced by nuclear or internal structure changes. Graphical Abstract